The retinoblastoma (Rb) and p53 genes are not essential for completion of the cell division cycle, but disruption of their functions is central to the life history of most, if not all, cancer cells (for review, see Weinberg 1995; Sherr 1996; Levine 1997). Surprisingly, Rb and p53 are themselves regulated by two proteins encoded by a single genetic locus, INK4a/ARF, the products of which, p16INK4a and p19ARF, are also potent tumor suppressors. The role of p16INK4a as an inhibitor of cyclin D-dependent kinases has been appreciated since its discovery (Serrano et al. 1993). Now, emerging evidence is providing valuable insights into the molecular circuitry through which p19ARF modulates p53 activity as part of a checkpoint response to oncogenic, hyperproliferative signals.